CONSUMPTION OF NIGHTSHADE , HUMAN HEALTH AND AUTOIMMUNE DISEASE

LOREN CORDAIN, PH.D. CONSUMPTION OF NIGHTSHADE PLANTS, HUMAN HEALTH AND AUTOIMMUNE DISEASE By Loren Cordain, Ph.D., Professsor

Previously, I have not specifically commented about Table 2. U.S. per capita nightshade consumption. Data from the nightshade family of plants in any of my three USDA Economic Research Service.2 books, however I have written a brief paper (Tomatoes, ITEM POUNDS YEAR and Autoimmune Disease) demonstrating Potatoes (total) 126.0 2007 a possible link between consumption and autoimmune disease. Frozen 53.0 2007 Fresh 44.0 2007 Nightshade is the common name for flowering plants belonging to the botanical family , which Chips 16.0 2007 contain more than 75 genera and 2,000 .1 Dehydrated 13.0 2007 Some notorious non-edible nightshades include Fresh Tomatoes 18.5 2008 tobacco, petunias, jimson weed, mandrake, and deadly nightshade. The family comprises well known food Processed Tomatoes 67.2 2008 plants such as potatoes, tomatoes, green peppers, (total) chili peppers, and tomatillos. Note that Tomato sauces 23.5 2008 chili peppers include all varieties of peppers from the Tomato paste 12.1 2008 genus , including bell peppers, jalapeno, wax, cayenne, , Anaheim, Thai, Tabasco, cherry, Whole tomatoes 11.4 2008 pepperoncini and Serrano among others. Chili peppers (Canned) are commonly consumed as dried powders such as Catsup 10.1 2008 , chili powder and cayenne, and are near Tomato juice 10.1 2008 universal ingredients in hot sauces, Tabasco sauces, and salsas. Some more obscure edible plants from the Bell peppers 9.1 2008 Solanaceae family are listed in Table 1. Chili peppers 6.4 2008 Table 2 shows the recent per capita consumption of 0.8 2008 commonly eaten nightshades. Potatoes come in first TOTAL 228.0 2008 (126 lbs) followed by tomatoes (85.7 lbs, including both fresh and processed), peppers (15.5 lbs) and eggplant (0.8 lbs). These figures clearly show that nightshades are a staple food, universally consumed in the U.S. diet. This raises the question: Are there any health hazards associated with eating almost 230 pounds of nightshades on a yearly basis?

2 Table 1. Some obscure and infrequently consumed edible foods within the Solanaceae family (adapted from: United States Department of Agriculture, Agricultural Research Service, Beltsville Area, Germplasm Resources Information Network (GRIN). http://www.ars-grin.gov/cgi-bin/npgs/html/tax_search.pl

COMMON NAME OR NAMES SCIENTIFIC NAME Tamarillo, Tree tomato, Terong belanda Cyphomandra betacea Goji , Wolfberry Lycium barbarum Purple ground cherry, Chinese lantern Quincula lobata Chinese lantern, Winter cherry, Bladder cherry, alkekengi Strawberry cherry Cut leaf ground cherry Physalis angulata Hairy ground-cherry, Dwarf cape gooseberry Physalis grisea Cape gooseberries, Golden berry, Husk cherry, Physalis peruviana Peruvian ground cherry, Poha berry, Giallo grosso Tomatillo, husk tomato Physalis philadelphica (formerly Physalis ixocarpa) Husk tomato, Strawberry tomato, Ground cherry Physalis pubescens Sticky gooseberry, Sticky Physalis Physalis viscose Gilo, Kumpa, Scarlet eggplant aethiopicum American nightshade, Black nightshade Solanum americanum Tzimbalo Solanum caripense Kangaroo apple Solanum laciniatum Indian nightshade Solanum lasiocarpum Garden huckleberry Solanum melanocerasum Pepino melon Lulo, Naranjilla Cocona, Orinoco-apple, Peach-tomato Solanum sessiliflorum Wonderberry, Sunberry Solanum retroflexum (formerly Solanum X burbankii) Ashwagandha, Withania, Winter cherry, Indian Withania somnifera winter cherry, Indian

3 POTATOES into other compounds by reacting with water). are commonly called glycoalkaloids. Let’s first examine potatoes. Potatoes generally maintain one of the highest glycemic index and load Both categories of saponins are widely distributed values of any food.3-6 Regular consumption of high throughout the plant kingdom including many glycemic index may promote obesity and cultivated crops. The primary function of saponins diseases of insulin resistance, including type 2 diabetes, is to protect the plant from microbial and insect cardiovascular disease, abnormal blood lipids, gout, attack by dissolving cell membranes of these potential acne, polycystic ovary syndrome, epithelial cell cancers (breast, colon and prostate), acanthosis nigricans (a Figure 1. The proposed mechanism by which dietary saponins may skin disease), and male vertex balding.7 Consequently elicit pores in intestinal cells leading to a “leaky gut”.9 in both of my books I do not recommend that potatoes be included as a regular component of Paleo Diets. Saponins Additionally, as you can see from Table 1, most of the potatoes consumed in the U.S. are highly processed in the form of french fries, mashed potatoes, dehydrated products, and potato chips. Processed potato foods typically are made with multiple additives (salt, vegetable oils, trans , refined , dairy products, cereal grains, preservatives, and other food additives) that may adversely affect health in a variety of ways. An additional nutritional property of potatoes that is rarely considered in regard to human health is their saponin content. Saponins derive their name from predators.8 In mammals, including humans who their ability to form “soap” like foams when mixed consume saponin containing plants, these substances with water. Chemically, saponins are classified as frequently create pores in the gut lining, thereby either steroid glycosides or triterpenoid glycosides. increasing intestinal permeability.8-10 If they enter the A is any of a group of organic compounds bloodstream in sufficient concentrations, they cause occurring abundantly in plants that yield a and hemolysis (destruction of the ) of red one or more non-sugar substances upon hydrolysis blood cells.8-10 (chemical decomposition in which a compound is split Figure 1 shows how saponins disrupt cell membranes which may lead to a leaky gut. Saponins first bind cholesterol molecules in intestinal cell membranes due to the affinity of a saponin component (the aglycone moiety) for the membrane (cholesterol).9 In the series of steps that follows, you can see how saponins cause portions of the cell membrane to buckle and eventually break free, forming a pore or a hole in the membrane. Potatoes contain two glycoalkaloid saponins: α-chaconine and α- which may adversely affect intestinal permeability and aggravate inflammatory bowel disease.11, 12 Even in normal healthy adults, a meal of mashed potatoes results in the rapid appearance of both α-chaconine and α-solanine in the bloodstream.13 The toxicity of these two glycoalkaloids is dose dependent – meaning that the greater the concentration in the bloodstream, the greater is their toxic effect. At least 12 separate

4 cases of human poisoning from potato consumption, Other researchers state: “Available information suggest involving nearly 2000 people and 30 fatalities have that the susceptibility of humans to glycoalkaloids been recorded.10 Potato saponins can be lethally toxic poisoning is both high and very variable: oral doses in once in the bloodstream in sufficient concentrations the range 1 - 5 mg/kg body weight are marginally to because these glycoalkaloids inhibit a key enzyme severely toxic to humans whereas 3 - 6 mg/kg body (acetyl cholinesterase) required for the synthesis of weight can be lethal. The narrow margin between acetylcholine, a neurotransmitter required for nerve toxicity and lethality is obviously of concern. Although impulse conduction.10 The concentration of both serious glycoalkaloid poisoning of humans is rare, α-chaconine and α- solanine in a variety of potato there is a widely held suspicion that mild poisoning is foods are listed in Table 3. Note that the highest more prevalent than supposed.” 10 concentrations of these toxic glycoalkaloids appear in potato foods containing the skins The commonly accepted safe limit for total (α-chaconine + α-solanine) in potato foods is 200 mg/ Table 3. Concentrations (mg/kg) of total glycoalkaloids kg, a level proposed more than 70 years ago, whereas (α-chaconine + α-solanine) in a variety of potato foods.10 more recent evidence suggests this level should be lowered to 60 – 70 mg/kg.10 If you take a look at Table Food Item α-chaconine + α-solanine 2 you can see that many potato food products exceed (mg/kg) this recommendation. Fried skins 567-1450 I believe that far more troubling than the potential Chips with skins 95 - 720 toxicity of potato glycoalkaloids is their potential to increase intestinal permeability over the course of Chips (US potatoes) 23 - 180 a lifetime, most particularly in people with diseases of chronic inflammation (cancer, autoimmune Frozen baked potatoes 80 - 123 disease, cardiovascular disease and diseases of insulin Frozen skins 65 - 121 resistance). A leaky gut has been recently proposed to be a universal initiating trigger for autoimmune Baked potato w/jacket 99 - 113 diseases14 – a conclusion that I agree with,15 as well as promoting cardiovascular disease16, 17 and diseases of Dehydrated potato flour 65 - 75 insulin resistance.18 When the gut becomes “leaky” Boiled peeled potato 27 - 42 it is not a good thing, as the intestinal contents may then have access to the immune system which in turn Canned whole new potatoes 24 - 34 becomes activated thereby causing a chronic low level systemic inflammation known as endotoxemia.16– 18 In Frozen fried potato 4 - 31 particular a component of the cell walls of gut gram Frozen French fries 2 - 29 Dehydrated potato flakes 15 - 23 French fries 0.4 - 8 Frozen mashed potatoes 2 - 5 Canned peeled potato 1 - 2 So the next logical question arises: Should we be eating a food that contains two known toxins which rapidly enter the bloodstream, increase intestinal permeability and potentially impair the nervous system? In the opinion of these authors: “. . . if the potato were to be introduced today as a novel food it is likely that its use would not be approved because of the presence of these toxic compounds.” 11

5 negative bacteria called lipopolysaccharide (LPS) is anti-nutrient called tomato lectin (TL) which rapidly highly inflammatory. Any LPS which gets past the crosses the gut barrier and enters into the bloodstream gut barrier is immediately engulfed by two types of in humans.28 The concentration of TL in tomatoes and immune system cells (macrophages and dendritic tomato products is between 3.0 – 6.0 mg/kg29. More cells). Once engulfed by these immune cells, LPS recently, TL has been employed by the pharmaceutical binds to a receptor (toll- like receptor-4) on these cells industry to experimentally deliver large molecular causing a cascade of effects leading to increases in weight across the gut barrier.30, 31 blood concentrations of pro-inflammatory cytokines (localized hormones) including interferon gamma The simultaneous presence of a saponin and a lectin (INF-γ),interleukin 1 (IL- 1), IL-6, IL-8 and tumor capable of binding gut tissue has an additive effect 32 necrosis factor alpha (TNF-α)16, 19. Two recent upon intestinal permeability. Hence, certain tomatoes human studies have shown that high potato diets and tomato food products contain both saponins and increase the blood inflammatory marker IL-620, 21. a lectin which compromise intestinal function and Without chronic low level systemic inflammation, it is promote a “leaky gut.” No dietary interventions have unlikely that few of the classic diseases of civilization ever been carried out in living humans to determine (cancer, cardiovascular disease, autoimmune diseases if tomato or potato consumption may adversely affect and diseases of insulin resistance) would have an the immune system and promote inflammation, opportunity to take hold and wreak their fatal effects. autoimmune disease and other chronic inflammatory diseases. A final note on potatoes – to add insult to injury, this commonly consumed food is a major source of dietary TOMATOES AND AUTOIMMUNE DISEASES lectins. On average potatoes contain 65 mg of potato Having said this, a convincing body of literature from lectin per kilogram. As is the case with most lectins, animal studies shows that α-tomatine is a powerful they have been poorly studied in humans, so we really stimulator of the immune response – so much so don’t have conclusive information how potato lectin that it is employed in vaccines as an adjuvant. Any may impact human health. However, preliminary substance which increases the potency of a is tissue studies indicate that potato lectin resists called an adjuvant. Autoimmune diseases and vaccines degradation by gut enzymes, bypasses the cell wall have numerous immunological similarities: vaccines 22,23 barriers and can then bind various tissues. Potato “pre-program” the immune system using elements lectins have been found to irritate the immune system within the vaccine to attack a foreign invader; whereas and produce symptoms of food hypersensitivity in autoimmune diseases result in the immune system 24 allergenic and non-allergenic patients. Just say “no” attacking one or more of the body’s own tissues. to potatoes!! TOMATOES In addition to potatoes, tomatoes represent another nightshade which increases intestinal permeability.25 The primary tomato saponin which causes a leaky gut is the glycoalkaloid, α-tomatine. Table 4 below shows the concentration of α-tomatine in a variety of tomatoes and tomato food products. Note that smaller and unripe tomatoes have noticeably increased concentrations of α-tomatine, whereas this compound is barely detectable in a standard ripe, red tomato. In contrast, ketchup, green , pickled green tomatoes and cherry tomatoes are all concentrated sources of α-tomatine. Although tomatoes typically maintain lower concentrations of glycoalkaloids than potatoes, they are more potent than potatoes in disrupting the intestinal membrane and promoting a “leaky gut”.27 In addition to α-tomatine, tomatoes contain another 6 Table 4. α-tomatine concentrations (mg/kg) in tomatoes and tomato Before I can address how tomatoes may be involved food products.26 with autoimmune diseases, I’ve got to briefly explain how vaccines and adjuvants work. The immune Type of Tomato or α-tomatine concentration response is normally a healthy reaction because Tomato Product (mg/kg) it allows our bodies to detect foreign antigens 1. Unripe, small immature green 548.0 (proteins) derived from invading microbes and take appropriate steps via the immune system to destroy 2. Unripe medium immature green 169.0 these organisms. Medicine has taken advantage of this naturally occurring response and has utilized it 3. Pickled green tomatoes (Brand A) 71.5 to prevent diseases in the form of vaccines. With a 4. Unripe pickled green 28.0 typical vaccine, dead or weakened microorganisms are injected into the body with a hypodermic needle 5. Pickled green tomatoes (Brand B) 28.0 and syringe. The immune system then recognizes the 6. Green salsa 27.5 vaccine antigens as foreign and destroys them, and in the process learns to “remember” them. When the 7. Sundried red tomatoes 21.0 “real” (virulent) version of the vaccine antigen appears, the immune system recognizes the invading microbe 8. Unripe green large 16.0 and destroys it thereby preventing the disease. With an 9. Unripe large immature green 10.0 autoimmune disease, it is as if this very same process occurs, except that the immune response is directed at 10. Sungold cherry tomatoes 11.0 one or more of the body’s own tissues or organs. 11. Fried Green tomatoes 11.0 When immunologists first began to manufacture vaccines they realized that many vaccines simply didn’t 12. Microwaved green tomatoes 11.0 work with weakened viruses or bacteria alone. They 13. Yellow cherry tomatoes 9.7 simply didn’t “rev” up the immune system sufficiently to result in a full blown immune response. It was 14. Ketchup 8.6 eventually discovered that by mixing weakened or dead microbes with another compound called 15. Red Sauce 5.7 an adjuvant the effectiveness of the vaccine was 16. Yellow pear cherry tomatoes 4.5 increased and full immunity could be established. The three most commonly used adjuvants are 1) 17. Tomato juice 2.8 alum (aluminum hydroxide), 2) Freund’s adjuvant (an antigen solution emulsified in oil, used as 18. Red cherry tomatoes 2.7 an immunopotentiator or compound that boosts the 19. Condensed tomato soup 2.2 immune system) and 3) Incomplete Freund’s adjuvant (the same adjuvant, but without the mycobacterial 20. Red pear cherry tomatoes 1.3 components). Of these three, only alum is licensed 21. Medium yellow tomatoes 1.3 for human use; the other two are used primarily in animals. 22. Large yellow tomatoes 1.1 So from what I’ve explained, you might expect it 23. Stewed canned tomatoes 1.1 possible for scientists to cause autoimmune diseases by creating vaccines containing some of the body’s 24. Ripe red beefsteak tomato 0.9 own tissues (antigens). Clearly, it would be unethical 25. Green zebra tomatoes 0.6 to deliberately cause an autoimmune disease in humans, but experiments in animals confirm that 26. Roma 0.4 organ specific autoimmune diseases can be caused by injecting a self-antigen with a powerful adjuvant 27. Standard red ripe tomato 0.3 such as Freund’s.33, 34 Neither the adjuvant alone nor the self-antigen typically results in autoimmunity in animals.33-35 Now the question arises, is it possible that

7 we can unknowingly be exposed to “natural” vaccines if they administered the foreign antigen containing (containing pathogens plus adjuvants) that trick our capsule along with an adjuvant, they could now immune systems into developing immunity against prevent oral tolerance by dendritic cells and cause a full our own tissues? blown immune response.36-38 So if a gut borne antigen is simultaneously present with a gut borne adjuvant, As immunologists further developed vaccines, instead the stage is set for promoting an immune response of injecting the foreign antigen with a hypodermic that may lead to an autoimmune disease if molecular needle through the skin, they attempted to initiate an mimicry exists between the gut borne antigen and one immune response by having subjects swallow a capsule of the body’s own tissues. containing the foreign antigen. Invariably, these experiments failed because dendritic cells in the gut Of the common autoimmune diseases (Table 5), which normally process foreign antigens did not elicit infectious agents such as viruses and bacteria are an immune response, but rather were nonreactive. thought to be the most likely environmental trigger.39 This nonreactive state by dendritic cells is actually the How viruses and bacteria ultimately set off an normal or default response called oral tolerance, and autoimmune response is not completely understood, prevents immune responses to non-harmful dietary but many scientists40-42 (including me15) believe it is and microbial antigens. Immunologists discovered that through a process called molecular mimicry whereby

Table 5. Common autoimmune diseases.

DISEASE TISSUE/ORGAN AFFECTED PREVALENCE Alopecia areata Hair follicle 170 per 100,000 Ankylosing spondylitis Spine and sacroiliac joints 129 per 100,000 Autoimmune urticaria Skin 330 per 100,000 Celiac disease Small intestine 400 per 100,000 Crohn’s disease Gastrointestinal tract 184 per 100,000 Diabetes (type 1) Pancreas 120 per 100,000 Graves’ disease Thyroid gland 1,120 per 100,000 Hashimoto’s thyroiditis Thyroid gland 9,460 per 100,000 Lupus erythematosis Any tissue in the body 510 per 100,000 Multiple sclerosis Central nervous system 140 per 100,000 Psoriasis Skin 2,020 per 100,000 Rheumatoid arthritis Joints 920 per 100,000 Scleroderma Skin, many other organs 110 per 100,000 Sjögren’s syndrome Salivary and tear glands 370 per 100,000 Ulcerative colitis Colon 35-100 per 100,000 Uveitis Anterior eye 850 per 100,000 Vitiligo Skin 740 per 100,000

8 amino acid sequences from viruses and bacteria facilitating the first step for entry of microbe antigens resemble amino acid sequences in our body’s organs and food antigens into circulation.14, 15 and tissues (see Figure 2). This similarity in molecular structure between infectious agents and our body’s An emerging consensus among scientists who study own tissues sometimes confuses certain components autoimmune disease is that a number of autoimmune of the immune system causing “self tolerance” to break diseases (including type 1 diabetes, Crohn’s disease, down, thereby resulting in the destruction of tissues dermatitis herpetiformis, rheumatoid arthritis, and organs by the immune system. celiac disease, and ankylosing spondylitis) have an environmental trigger that originates from a leaky gut, Exposure to viruses, bacteria and other microbes most thereby allowing microbe and food antigens continual typically occurs in a number of ways: 1) the microbe access to the immune system.14, 15, 44, 45 may enter your body through mucous membranes in your nose, mouth or gastrointestinal or genitourinary As I have previously outlined, tomatoes contain tracts, or 2) it enters your body through a break in two (tomato lectin and α-tomatine) your skin caused by a wound or insect/vector bite. On which increase intestinal permeability. Additionally, a daily basis, we are regularly exposed to microbes both of these compounds may simultaneously bind via all of these pathways, however far and away the the cell walls of various gut bacteria, viruses and greatest regular exposure to microbes comes from partially digested bacteria/viruses thereby forming 43 In complexes containing: 1. tomato lectin + viral or viruses and bacteria that reside in our intestines. 46, 47 healthy people the gut tissue represents a powerful bacterial antigen and/or 2. α-tomatine + viral barrier that prevents microorganisms within the gut or bacterial antigen. In other words, both tomato from entering the bloodstream. Additionally, certain lectin and α-tomatine may act as a “Trojan Horse,” components of the immune system and the liver act thereby causing the intestines to become leaky while to prevent proteins (antigens) from gut microbes simultaneously binding to and pulling bacterial from entering circulation. However, under certain and viral antigens past the gut barrier. A healthy immune system response to these foreign antigens circumstances gut permeabilityFigure may increase 2. thereby Schematic representation of the molecular mimicry process. Figure 2. Schematic representation of the molecular mimicry process.

Molecular Matches

Myelin Basic Protein: from nerve sheaths f s w g a e g q r

Escherichia coli Bacteria: f g w g a e l n m

Molecular Matches

9 is “oral tolerance” (ignoring) of these gut borne invaders. Botanically speaking, the of are However if an adjuvant is simultaneously present with berries. However, the peppers are considered these bacterial or viral antigens, then a full blown immune vegetables (bell peppers) or spices (e.g. cayenne response can occur. Well you guessed it, α-tomatine not pepper) for culinary purposes, based on factors only increases intestinal permeability but also is a powerful including fleshiness and intensity of flavor. immunological adjuvant48-54 used in the manufacture of vaccines. Similarly, tomato lectin acts as a potent 46 adjuvant. Table 6. Some common names for the five In the wild world of the internet and elsewhere, urban domesticated species of the Capsicum genus. legend has it that consumption of nightshade (tomato, COMMON NAME OR NAMES SCIENTIFIC NAME potato, eggplant, bell peppers, hot peppers, and paprika) free diets may improve symptoms in some rheumatoid , , arthritis patients.55, 56 Is there any scientific basis for Cherry pepper, , these alleged anecdotal observations? Indeed, in theory a Paprika, Jalapeno pepper, growing body of scientific studies points toward the use pimento, Serrano pepper of nightshade-free diets in the treatment of rheumatoid arthritis and other autoimmune diseases. To date, no Aji, Brown’s Pepper, animal or human experiments have been conducted that Peruvian pepper confirm or deny this hypothetical evidence. As has been Habanero chili, Bonnet my policy in the past, I believe that anyone suffering from pepper an autoimmune disease should remove suspect foods from the diet for an extended period and then monitor symptoms. If conditions get worse after you re-introduce Rocoto pepper the food, then this particular food may be problematic for you and should not be part of your lifelong diet.

Because the effects of saponins on membrane function and The sensory “heat” from chili peppers comes from a intestinal permeability are dose dependent,25, 27 then the group of compounds called capsaicinoids. More than more saponins you consume the greater the potential for 20 capsaicinoids are found in chili peppers, and their your gut to become leaky. To date, little is known about concentrations range from 0% by weight to more the dietary threshold concentrations of saponins required than 2% by weight.60 Daily per capita consumption to elicit a leaky gut in humans and its associated adverse of capsaicinoids from chili peppers in the U.S. health effects. My recommendation for healthy people and Europe is ~1.5 mg, whereas in India, would be to avoid potatoes for all of the reasons I have and Thailand it is ~25-200 mg.60 Chili peppers are previously listed. However, because ripe red tomatoes have favorite spices throughout the world because of their such low concentrations of α-tomatine, and because they pungent or “hot” and aroma. So, the greater the are rich sources of , minerals and other healthful concentration of capsaicinoids in the chili pepper, the nutrients, only people with an autoimmune disease or “hotter” it . Table 7 shows the concentrations of allergies should consider limiting their fresh ripe tomato total capsaicinoids in a variety of chili peppers and intake. chili pepper containing foods. CHILI PEPPERS All chili peppers belong to the genus Capsicum (family Solanaceae) and are among the most heavily consumed spices throughout the world.57 There are 22 wild species within the Capsicum genus, and five domesticated species,58 of which more than 200 or more varieties have been produced depending upon various environmental factors to which the plants are exposed.59 Table 6 shows the five domesticated species and lists a few of the more common varieties of chili peppers. 10 Table 7. Concentrations of total capsaicinoids in a variety of chili peppers and chili pepper containing foods.60

PEPPER/FOOD PRODUCT TOTAL CAPSAICINOID CONTENT (MICROGRAM/G) McCormick ground cayenne pepper 3,588 Habanero pepper, fresh 2,261 Thai pepper, fresh 1333 McCormick original chili seasonings 830 McIlhenny hot habanero sauce 547 Hungarian hot paprika 439 La Costena Chipotle, whole, canned 416 McCormick hot taco seasoning 394 Mezzetta hot chili, canned 306 La Costena jalapeno green whole pickledcanned 210 Lawry Choula hot sauce 201 Capsaicinoids seem to have both beneficial and deleterious health effects.60, 61 They have long been McIlhenny Tabasco original hot sauce 195 used in Mayan and Ayurvedic therapeutic remedies62 McCormick mild taco seasoning 186 and more recently have found therapeutic application in pain relief.63 Lawry Crystal hot sauce, extra hot 174 One of the potential shortcomings of chili peppers is La Costena seranno, green whole pickled their ability to increase intestinal permeability64-69 - canned 164 and this may be their greatest threat to human health. As far back as 1998 it was suggested that chili peppers Star Foods pepperoncini canned 82 - because of their capsaicinoids - “may modulate the Serrano, fresh 77 absorption of low molecular weight food constituents that are involved in the pathogenesis of food allergy Green jalapeno, fresh 76 and intolerance”. 69 More recently, many scientists now believe that increased intestinal permeability, Red jalapeno, fresh 46 often times called “leaky gut” represents a universal Safeway hot pepper sauce 45 environmental triggering event for autoimmune diseases.14, 15, 44, 45 As stated earlier, when the gut Mezzetta sliced jalapeno, canned 19 becomes “leaky” it is not a good thing, as the intestinal contents may then have access to the immune system Green, red and yellow bell peppers, fresh 0 (which in turn becomes activated), thereby causing a Roasted red canned 0 chronic low level systemic inflammation known as endotoxemia16 – 18 that may promote cardiovascular Roasted green canned 0 disease16, 17 and diseases of insulin resistance.18 To date, Whole canned peppers 0 this chain of physiological events (e.g. consumption of chili peppers increases intestinal permeability which increases low level inflammation, which increases the risk for disease) has not yet been demonstrated in living (in vivo) humans. As always, I believe that 11 anyone suffering from an autoimmune disease should 7. Cordain L, Eades MR, Eades MD. Hyperinsulinemic remove suspect foods from the diet for an extended diseases of civilization: more than just Syndrome X. period and then monitor symptoms. If conditions Comp Biochem Physiol A Mol Integr Physiol. 2003 get worse after you re-introduce the food, then this Sep;136(1):95-112. particular food may be problematic for you and should not be part of your lifelong diet. 8. Francis G, Kerem Z, Makkar HP, Becker K. The biological action of saponins in animal systems: a SUMMARY review. Br J Nutr. 2002 Dec;88(6):587-605. In the U.S. we consume almost 230 pounds of 9. Keukens EA, de Vrije T, van den Boom C, de nightshades per person on a yearly basis. These Waard P, Plasman HH, Thiel F, Chupin V, Jongen common foods (potatoes, tomatoes, chili peppers, WM, de Kruijff B.. Molecular basis of glycoalkaloid and eggplants) have become such staples in our diets induced membrane disruption. Biochim Biophys Acta that few people rarely - if ever - consider that they are 1995;1240: 216-228. very recent additions to worldwide human nutrition. In fact, prior to 1492 and Columbus’ “discovery” of 10. Smith DB, Roddick JG, Jones JL. Potato the new world, no Europeans, Middle Easterners, glycoalkaloids: some unanswered questions. Trends in Africans or Asians ever had access to these foods, Food Sci Technol 1996;7:126-131. as they are all indigenous to Central and South 11. Patel B, Schutte R, Sporns P, Doyle J, Jewel L, America. Hence, humanity as a whole has had very Fedorak RN. Potato glycoalkaloids adversely affect little evolutionary experience with foods that contain intestinal permeability and aggravate inflammatory multiple toxins (saponins and lectins primarily), which bowel disease. Inflamm Bowel Dis. 2002 cause numerous adverse health effects in humans and Sep;8(5):340-6. animals. For Paleo Dieters my advice would to be to eliminate or drastically reduce potato consumption 12. Iablokov V, Sydora BC, Foshaug R, Meddings and for autoimmune and allergy patients to be cautious J, Driedger D, Churchill T, Fedorak RN. Naturally with the consumption of tomatoes, chili peppers and occurring glycoalkaloids in potatoes aggravate eggplants. intestinal inflammation in two mouse models of inflammatory bowel disease. Dig Dis Sci. 2010 Mar 3. [Epub ahead of print] REFERENCES 13. Hellenäs KE, Nyman A, Slanina P, Lööf L, 1. Heiser CB. Nightshades, the Paradoxical Plants. Gabrielsson J. Determination of potato glycoalkaloids W.H. Freeman and Company, San Francisco, CA, 1969. and their aglycone in blood serum by high- performance liquid chromatography. Application to 2. USDA, Economic Research Service. http://www.ers. pharmacokinetic studies in humans. J Chromatogr. usda.gov/ 1992 Jan 3;573(1):69-78. 3. Foster-Powell K, Holt SH, Brand-Miller JC. 14. Fasano A. Surprises from celiac disease. Sci Am. International table of glycemic index and glycemic load 2009 Aug;301(2):54-61. values: 2002. Am J Clin Nutr. 2002 Jul;76(1):5-56. 15. Cordain L, Toohey L, Smith MJ, Hickey MS. 4. Leeman M, Ostman E, Björck I. Glycaemic and Modulation of immune function by dietary lectins in satiating properties of potato products. Eur J Clin Nutr. rheumatoid arthritis. Br J Nutr. 2000 Mar;83(3):207-17. 2008 Jan;62(1):87-95. 16. Stoll LL, Denning GM, Weintraub NL. Endotoxin, 5. Fernandes G, Velangi A, Wolever TM. Glycemic TLR4 signaling and vascular inflammation: potential index of potatoes commonly consumed in North therapeutic targets in cardiovascular disease. Curr America. J Am Diet Assoc. 2005 Apr;105(4):557-62. Pharm Des. 2006;12(32):4229-45. 6. Henry CJ, Lightowler HJ, Strik CM, Storey 17. Rauchhaus M, Coats AJ, Anker SD. The M. Glycaemic index values for commercially endotoxin-lipoprotein hypothesis. Lancet. 2000 Sep available potatoes in Great Britain. Br J Nutr. 2005 9;356(9233):930-3. Dec;94(6):917-21.

12 18. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf tissue preparations. Toxicol in Vitro 1996;10:117-128. C, Bastelica D et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007 28. Kilpatrick DC, Pusztai A, Grant G, Graham C, Jul;56(7):1761-72. Ewen SW. Tomato lectin resists digestion in the mammalian alimentary canal and binds to intestinal 19. Sweet MJ, Hume DA. Endotoxin signal villi without deleterious effects. FEBS Lett. 1985 Jun transduction in macrophages. J Leukoc Biol 1996;60: 17;185(2):299-305. 8- 26. 29. Nachbar MS, Oppenheim JD, Thomas JO. Lectins 20. Kallio P, Kolehmainen M, Laaksonen DE, in the U.S. Diet. Isolation and characterization of a Pulkkinen L, Atalay M, Mykkänen H, Uusitupa M, lectin from the tomoto (Lycopersicon esculentum). J Poutanen K, Niskanen L. Inflammation markers Biol Chem 1980;2056-2061. are modulated by responses to diets differing in postprandial insulin responses in individuals with 30. Bies C, Lehr CM, Woodley JF. Lectin-mediated the metabolic syndrome. Am J Clin Nutr. 2008 targeting: history and applications. Adv Drug May;87(5):1497-503. Deliv Rev. 2004 Mar 3;56(4):425-35. 21. Naruszewicz M, Zapolska-Downar D, Kośmider 31. Carreno-Gómez B, Woodley JF, Florence AT. A, Nowicka G, Kozłowska-Wojciechowska M, Studies on the uptake of tomato lectin nanoparticles in Vikström AS, Törnqvist M. Chronic intake of potato everted gut sacs. Int J Pharm. 1999 Jun 10;183(1):7-11. chips in humans increases the production of reactive 32. Alvarez JR, Torres-Pinedo R. Interactions of oxygen radicals by leukocytes and increases plasma lectin, soyasaponins, and glycinin with rabbit C-reactive protein: a pilot study. Am J Clin Nutr. 2009 jejunal mucosa in vitro. Pediatr Res 1982;16:728-31. Mar;89(3):773-7. 33. Fairweather D, Kaya Z, Shellam GR, Lawson 22. Gabor F, Stangl M, Wirth M. Lectin-mediated CM, Rose NR. From infection to autoimmunity. J bioadhesion: binding characteristics of plant lectins on Autoimmun. 2001 May;16(3):175-86. the enterocyte-like cell lines Caco-2, HT-29 and HCT- 8. J Control Release. 1998 Nov 13;55(2- 3):131-42. 34. Fairweather D, Frisancho-Kiss S, Rose NR. Viruses as adjuvants for autoimmunity: evidence from 23. Qaddoumi M, Lee VH. Lectins as endocytic Coxsackievirus-induced myocarditis. Rev Med Virol. ligands: an assessment of lectin binding and uptake to 2005 Jan-Feb;15(1):17-27. rabbit conjunctival epithelial cells. Pharm Res. 2004 Jul;21(7):1160-6. 35. Fairweather D, Rose NR. Women and autoimmune disease. Emerg Infect Dis 2004;10:2005- 2011. 24. Pramod SN, Venkatesh YP, Mahesh PA. Potato lectin activates basophils and mast cells of atopic 36. Mcl Mowat A. Dendritic cells and immune subjects by its interaction with core chitobiose of responses to orally administered antigens. Vaccine cell-bound non-specific immunoglobulin E. Clin Exp 2005;23:1797-99. Immunol. 2007 Jun;148(3):391-401. 37. Strobel S, Mowat MA. Oral tolerance and allergic 25. Johnson IT, Gee JM, Price K, Curl C, Fenwick responses to food proteins. Curr Opin Allergy Clin GR. Influence of saponins on gut permeability Immunol. 2006 Jun;6(3):207-13. and active nutrient transport in vitro. J Nutr. 1986 Nov;116(11):2270-7. 38. Benko S, Magyarics Z, Szabó A, Rajnavölgyi E. Dendritic cell subtypes as primary targets of vaccines: 26. Friedman M, Levin CE. Alpha tomatine content the emerging role and cross-talk of pattern recognition in tomato and tomato products determined by HPLC receptors. Biol Chem. 2008 May;389(5):469-85. with pulsed amperometric detection. J Agric Food Chem 1995;43:1507-1511. 39. Progress in Autoimmune Disease Research. The Autoimmune Disease Coordinating Committee 27. Gee JM, Wortley GM, Johnson It, Price KR, Rutten Report to Congress. U.S. Department of Health AA. Houben GF, Penninks, AJ. Effects of saponins and Human Services, National Institutes of Health, and glycoalkaloids on the permeability and viability National Institute of Allergy and Infectious Diseases. of mammalian intestinal cells and on the integrity of Bethesda (MD), 2005. http://www3.niaid.nih.gov/ 13 topics/autoimmune/PDF/ADCCFinal.pdf profiles in ovalbumin immunized mice.Vaccine. 1999 Aug 20;18(1-2):140-52. 40. Lee S, Levin MC. Molecular mimicry in neurological disease: what is the evidence? Cell Mol 53. Sheikh NA, Rajananthanan P, Attard GS, Morrow Life Sci. 2008 Apr;65(7-8):1161-75. WJ.Generation of antigen specific CD8+ cytotoxic T cells following immunization with soluble protein 41. Blank, M., Barzilai, O. and Shoenfeld, Y. (2007) formulated with novel glycoside adjuvants. Vaccine. Molecular mimicry and auto-immunity. Clin. Rev. 1999 Aug 6;17(23-24):2974-82. Allergy Immunol. 32, 111–118. 54. Rajananthanan P, Attard GS, Sheikh NA, Morrow 42. Albert, L. J. and Inman, R. D. (1999) Molecular WJ.Evaluation of novel aggregate structures as mimicry and autoimmunity. N. Engl.J. Med. 341, adjuvants: composition, toxicity studies and humoral 2068–2074. responses.Vaccine. 1999 Feb 26;17(7- 8):715-30. 43. O’Hara AM, Shanahan F. The gut flora as a 55. http://noarthritis.com/research.htm forgotten organ. EMBO Rep. 2006 Jul;7(7):688-93. 56. Childers NF. Arthritis - Childer’s Diet to Stop It. 44. Arrieta MC, Bistritz L, Meddings JB.Alterations in Nightshades, Aging and Ill Health, 4th ed. Florida: intestinal permeability. Gut. 2006 Oct;55(10):1512-20. Horticultural Publications, 1993. 45. Fasano A. Physiological, pathological, and 57. Govindarajan VS, Sathyanarayana MN.Capsicum- therapeutic implications of zonulin-mediated intestinal -production, technology, chemistry, and quality. Part barrier modulation: living life on the edge of the wall. V. Impact on physiology, pharmacology, nutrition, Am J Pathol. 2008 Nov;173(5):1243-52. and metabolism; structure, pungency, pain, and 46. Naisbett B, Woodley J. The potential use of desensitization sequences. Crit Rev Food Sci Nutr. tomato lectin for oral drug delivery: 4. Immunological 1991;29(6):435-74. consequences. Int J Pharm 1995;120:247-254. 58. Bosland PW. : history, cultivation, and uses. 47. De Aizpurua HJ, Russell-Jones GJ. Oral vaccination. In: Charalambous G (Ed.), Spices, Herbs and Edible Identification of classes of proteins that provoke Fungi (Herbs). Elsevier Science Publishers, Amsterdam, an immune response upon oral feeding. J Exp Med 1994, pp. 347-366. 1988;167:440-451. 59. Pruthi JS. Spices and Condiments. In: Chichester 48. Morrow WJ, Yang YW, Sheikh EM, Stewart GF (Eds), Academic Press, New York, NA.Immunobiology of the Tomatine adjuvant. 1980;p. 13. Vaccine. 2004 Jun 23;22(19):2380-4. 60. Kozukue N, Han JS, Kozukue E, Lee SJ, Kim JA, 49. Yang YW, Wu CA, Morrow WJ.The apoptotic and Lee KR, Levin CE, Friedman M. Analysis of eight necrotic effects of tomatine adjuvant. Vaccine. 2004 capsaicinoids in peppers and pepper-containing foods Jun 2;22(17-18):2316-27. by high-performance liquid chromatography and liquid chromatography-mass spectrometry. J Agric Food 50. Yang YW, Sheikh NA, Morrow WJ.The Chem. 2005 Nov 16;53(23):9172-81. ultrastructure of tomatine adjuvant. Biomaterials. 2002 Dec;23(23):4677-86. 61. Surh YJ, Lee SS. in hot chili pepper: carcinogen, co-carcinogen or anticarcinogen? Fd Chem 51. Heal KG, Sheikh NA, Hollingdale MR, Morrow Toxic 1996;34:313-316. WJ, Taylor-Robinson AW. Potentiation by a novel glycoside adjuvant of a protective cytotoxic 62. Thapa B, Skalko-Basnet N, Takano A, Masuda K, T cell immune response specific for a preerythrocytic Basnet P. High-performance liquid chromatography malaria vaccine candidate antigen.Vaccine. 2001 Jul analysis of capsaicin content in 16 Capsicum 20;19(30):4153-61. from Nepal. J Med Food 2009;12:908-913. 52. Rajananthanan P, Attard GS, Sheikh NA, Morrow 63. Sasamura T, Kuraishi Y. Peripheral and central WJ.Novel aggregate structure adjuvants modulate actions of capsaicin and VR1 receptor. Jpn J Pharmacol lymphocyte proliferation and Th1 and Th2 cytokine 1999;80:275-280.

14 64. Isoda H, Han J, Tominaga M, Maekawa T. Effects of capsaicin on human intestinal cell line Caco- 2. Cytotechnology. 2001 Jul;36(1-3):155-61. 65. Han J, Isoda H, Maekawa T. Analysis of the mechanism of the tight-junctional permeability increase by capsaicin treatment on the intestinal Caco- 2 cells. Cytotechnology. 2002 Nov;40(1-3):93-8. 66. Han JK, Akutsu M, Talorete TP, Maekawa T, Tanaka T, Isoda H. Capsaicin-enhanced Ribosomal Protein P2 Expression in Human Intestinal Caco-2 Cells. Cytotechnology. 2005 Jan;47(1-3):89- 96. 67. Komori Y, Aiba T, Nakai C, Sugiyama R, Kawasaki H, Kurosaki Y. Capsaicin-induced increase of intestinal cefazolin absorption in rats. Drug Metab Pharmacokinet. 2007 Dec;22(6):445-9. 68. Tsukura Y, Mori M, Hirotani Y, Ikeda K, Amano F, Kato R, Ijiri Y, Tanaka K. Effects of capsaicin on cellular damage and monolayer permeability in human intestinal Caco-2 cells. Biol Pharm Bull. 2007 Oct;30(10):1982-6. 69. Jensen-Jarolim E, Gajdzik L, Haberl I, Kraft D, Scheiner O, Graf J. Hot spices influence permeability of human intestinal epithelial monolayers. J Nutr. 1998 Mar;128(3):577-81.

15